| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Yoshimasa Tottori University Hospital, Assistant Professor, 医学部附属病院, 助手 (00335514)
OHUGI Shigetstugu Tottori University, Professor, 医学部附属病院, 教授 (50168845)
本多 祐 鳥取大学, 医学部・附属病院, 助手 (90325019)
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| Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Research Abstract |
Matrix metalloproteinases (MMPs) and Tissue Inhibitor of Metalloproteinases (TIMPs) play important roles in the mechanism of abdominal aortic aneurysms (AAAs) progression and pathological vascular remodeling is considered to be mediated by MMPs, which are secreted by invasive macrophages, migrating vascular smooth muscle cells (VSMCs) and endothelial cells. In this study, we examined the pathogenesis of AAAs with respect to pathological characteristics and expression of MMPs and TIMPs in the human AAA specimens and cultured cells. These expressions were evaluated by immunohistochemistry, competitive PCR, and western blotting.
First, we investigated the expression of MMPs and TIMPs in the wall of human abdominal aortic aneurysms. Small AAA tend to have high expression of MMP-2, 9 and12, the other side, large AAA tend to high expression of MMP-9, 12 and 14. Immunohistochemistry showed MMP-2 and TIMP-1 positive cells mainly in the intima, and MMP-9 positive cells in the intima and adventitia. Moreover, the macrophages migrated in the adventitia of the aneurismal wall and they were positive for MMP-12. The mRNA and protein levels significantly correlated between MMP-2 and 9, or MMP-9 and TIMP-1. Second, we investigated the expression of MMP-2 and 9 in the cultured human VSMCs and the cultured human macrophages. The expression of MMP-2 increased in the VSMCs by the stimulation of some cytokines (IL-1 beta, 3, 6, and TNF-alpha), the other side, the macrophages produced no MMP-2 and 9.
These results indicated the cooperative action between MMP-2 and 9, further MMP-9 and 12, and these enzymes might play a crucial role in the development of AAAs, and the inhibitory action of TIMP-1 against MMP-2 and 9 in the AAAs wall. Moreover, the VSMCs participated in the expression of MMP-2 and the macrophages participated in the expression of MMP-12. These cells might play pivotal roles in the mechanisms of AAAs progression.
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